RNA-mediated gene regulation is less evolvable than transcriptional regulation

Much of gene regulation is carried out by proteins that bind DNA or RNA molecules at specific sequences. One class of such proteins is transcription factors, which bind short DNA sequences to regulate transcription. Another class is RNA binding proteins, which bind short RNA sequences to regulate RNA maturation, transport, and stability. Here, we study the robustness and evolvability of these regulatory mechanisms. To this end, we use experimental binding data from 172 human and fruit fly transcription factors and RNA binding proteins as well as human polymorphism data to study the evolution of binding sites in vivo. We find little difference between the robustness of regulatory protein–RNA interactions and transcription factor–DNA interactions to DNA mutations. In contrast, we find that RNA-mediated regulation is less evolvable than transcriptional regulation, because mutations are less likely to create interactions of an RNA molecule with a new RNA binding protein than they are to create interactions of a gene regulatory region with a new transcription factor. Our observations are consistent with the high level of conservation observed for interactions between RNA binding proteins and their target molecules as well as the evolutionary plasticity of regulatory regions bound by transcription factors. They may help explain why transcriptional regulation is implicated in many more evolutionary adaptations and innovations than RNA-mediated gene regulation.

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Regulation of Fetal Genes by Transitions among RNA-Binding Proteins during Liver Development

International Journal of Molecular Sciences ◽

10.3390/ijms21239319 ◽

2020 ◽

Vol 21 (23) ◽

pp. 9319

Author(s):

Toru Suzuki ◽

Shungo Adachi ◽

Chisato Kikuguchi ◽

Shinsuke Shibata ◽

Saori Nishijima ◽

...

Keyword(s):

Transcriptional Regulation ◽

Binding Proteins ◽

Rna Binding ◽

Rna Binding Proteins ◽

Fetal Liver ◽

Regulatory Protein ◽

Rna Decay ◽

Translation Efficiency ◽

Mrna Binding ◽

Post Transcriptional Regulation

Transcripts of alpha-fetoprotein (Afp), H19, and insulin-like growth factor 2 (Igf2) genes are highly expressed in mouse fetal liver, but decrease drastically during maturation. While transcriptional regulation of these genes has been well studied, the post-transcriptional regulation of their developmental decrease is poorly understood. Here, we show that shortening of poly(A) tails and subsequent RNA decay are largely responsible for the postnatal decrease of Afp, H19, and Igf2 transcripts in mouse liver. IGF2 mRNA binding protein 1 (IMP1), which regulates stability and translation efficiency of target mRNAs, binds to these fetal liver transcripts. When IMP1 is exogenously expressed in mouse adult liver, fetal liver transcripts show higher expression and possess longer poly(A) tails, suggesting that IMP1 stabilizes them. IMP1 declines concomitantly with fetal liver transcripts as liver matures. Instead, RNA-binding proteins (RBPs) that promote RNA decay, such as cold shock domain containing protein E1 (CSDE1), K-homology domain splicing regulatory protein (KSRP), and CUG-BP1 and ETR3-like factors 1 (CELF1), bind to 3′ regions of fetal liver transcripts. These data suggest that transitions among RBPs associated with fetal liver transcripts shift regulation from stabilization to decay, leading to a postnatal decrease in those fetal transcripts.

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Specific DNA sequences allosterically enhance protein–protein interaction in a transcription factor through modulation of protein dynamics: implications for specificity of gene regulation

Physical Chemistry Chemical Physics ◽

10.1039/c7cp01193h ◽

2017 ◽

Vol 19 (22) ◽

pp. 14781-14792

Author(s):

Abhishek Mazumder ◽

Subrata Batabyal ◽

Manas Mondal ◽

Tanumoy Mondol ◽

Susobhan Choudhury ◽

...

Keyword(s):

Gene Regulation ◽

Transcription Factor ◽

Transcription Factors ◽

Protein Dynamics ◽

Protein Interaction ◽

Dna Sequences ◽

Protein Complexes ◽

Regulatory Region ◽

Protein Protein Interaction ◽

Gene Regulatory

Most genes are regulated by multiple transcription factors, often assembling into multi-protein complexes in the gene regulatory region.

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Identification of Novel RNA Binding Proteins Influencing Circular RNA Expression in Hepatocellular Carcinoma

International Journal of Molecular Sciences ◽

10.3390/ijms22147477 ◽

2021 ◽

Vol 22 (14) ◽

pp. 7477

Author(s):

Rok Razpotnik ◽

Petra Nassib ◽

Tanja Kunej ◽

Damjana Rozman ◽

Tadeja Režen

Keyword(s):

Hepatocellular Carcinoma ◽

Binding Proteins ◽

Rna Binding ◽

Rna Binding Proteins ◽

Regulatory Protein ◽

Circular Rna ◽

Differentially Expressed ◽

Circular Rnas ◽

Bioinformatics Analyses ◽

Published Evidence

Circular RNAs (circRNAs) are increasingly recognized as having a role in cancer development. Their expression is modified in numerous cancers, including hepatocellular carcinoma (HCC); however, little is known about the mechanisms of their regulation. The aim of this study was to identify regulators of circRNAome expression in HCC. Using publicly available datasets, we identified RNA binding proteins (RBPs) with enriched motifs around the splice sites of differentially expressed circRNAs in HCC. We confirmed the binding of some of the candidate RBPs using ChIP-seq and eCLIP datasets in the ENCODE database. Several of the identified RBPs were found to be differentially expressed in HCC and/or correlated with the overall survival of HCC patients. According to our bioinformatics analyses and published evidence, we propose that NONO, PCPB2, PCPB1, ESRP2, and HNRNPK are candidate regulators of circRNA expression in HCC. We confirmed that the knocking down the epithelial splicing regulatory protein 2 (ESRP2), known to be involved in the maintenance of the adult liver phenotype, significantly changed the expression of candidate circRNAs in a model HCC cell line. By understanding the systemic changes in transcriptome splicing, we can identify new proteins involved in the molecular pathways leading to HCC development and progression.

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Evaluation of Post-transcriptional Gene Regulation in Pancreatic Cancer Cells: Studying RNA Binding Proteins and Their mRNA Targets

Methods in Molecular Biology - Pancreatic Cancer ◽

10.1007/978-1-4939-8879-2_22 ◽

2018 ◽

pp. 239-252 ◽

Cited By ~ 4

Author(s):

Aditi Jain ◽

Samantha Z. Brown ◽

Henry L. Thomsett ◽

Eric Londin ◽

Jonathan R. Brody

Keyword(s):

Pancreatic Cancer ◽

Gene Regulation ◽

Cancer Cells ◽

Binding Proteins ◽

Rna Binding ◽

Rna Binding Proteins ◽

Mrna Targets ◽

Pancreatic Cancer Cells ◽

Transcriptional Gene Regulation

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Roles of RNA-binding Proteins and Post-transcriptional Regulation in Driving Male Germ Cell Development in the Mouse

Advances in Experimental Medicine and Biology - RNA Processing ◽

10.1007/978-3-319-29073-7_6 ◽

2016 ◽

pp. 123-151 ◽

Cited By ~ 13

Author(s):

Donny D. Licatalosi

Keyword(s):

Transcriptional Regulation ◽

Germ Cell ◽

Binding Proteins ◽

Rna Binding ◽

Rna Binding Proteins ◽

Cell Development ◽

Male Germ Cell ◽

Germ Cell Development ◽

Post Transcriptional Regulation

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Post-transcriptional regulation in hematopoiesis: RNA binding proteins take control

Biochemistry and Cell Biology ◽

10.1139/bcb-2017-0310 ◽

2019 ◽

Vol 97 (1) ◽

pp. 10-20 ◽

Cited By ~ 7

Author(s):

Laura P.M.H. de Rooij ◽

Derek C.H. Chan ◽

Ava Keyvani Chahi ◽

Kristin J. Hope

Keyword(s):

Transcriptional Regulation ◽

Stem Cell ◽

Cell Fate ◽

Binding Proteins ◽

Rna Binding ◽

Rna Binding Proteins ◽

Control Of Gene Expression ◽

Hematopoietic Stem ◽

Cell Fate Decisions ◽

Post Transcriptional Regulation

Normal hematopoiesis is sustained through a carefully orchestrated balance between hematopoietic stem cell (HSC) self-renewal and differentiation. The functional importance of this axis is underscored by the severity of disease phenotypes initiated by abnormal HSC function, including myelodysplastic syndromes and hematopoietic malignancies. Major advances in the understanding of transcriptional regulation of primitive hematopoietic cells have been achieved; however, the post-transcriptional regulatory layer that may impinge on their behavior remains underexplored by comparison. Key players at this level include RNA-binding proteins (RBPs), which execute precise and highly coordinated control of gene expression through modulation of RNA properties that include its splicing, polyadenylation, localization, degradation, or translation. With the recent identification of RBPs having essential roles in regulating proliferation and cell fate decisions in other systems, there has been an increasing appreciation of the importance of post-transcriptional control at the stem cell level. Here we discuss our current understanding of RBP-driven post-transcriptional regulation in HSCs, its implications for normal, perturbed, and malignant hematopoiesis, and the most recent technological innovations aimed at RBP–RNA network characterization at the systems level. Emerging evidence highlights RBP-driven control as an underappreciated feature of primitive hematopoiesis, the greater understanding of which has important clinical implications.

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CELF RNA binding proteins promote axon regeneration in C. elegans and mammals through alternative splicing of Syntaxins

eLife ◽

10.7554/elife.16072 ◽

2016 ◽

Vol 5 ◽

Cited By ~ 13

Author(s):

Lizhen Chen ◽

Zhijie Liu ◽

Bing Zhou ◽

Chaoliang Wei ◽

Yu Zhou ◽

...

Keyword(s):

Gene Expression ◽

Transcriptional Regulation ◽

Alternative Splicing ◽

Binding Proteins ◽

Rna Binding ◽

Axon Regeneration ◽

Rna Binding Proteins ◽

Mrna Isoforms ◽

C Elegans ◽

Mrna Targets

Axon injury triggers dramatic changes in gene expression. While transcriptional regulation of injury-induced gene expression is widely studied, less is known about the roles of RNA binding proteins (RBPs) in post-transcriptional regulation during axon regeneration. In C. elegans the CELF (CUGBP and Etr-3 Like Factor) family RBP UNC-75 is required for axon regeneration. Using crosslinking immunoprecipitation coupled with deep sequencing (CLIP-seq) we identify a set of genes involved in synaptic transmission as mRNA targets of UNC-75. In particular, we show that UNC-75 regulates alternative splicing of two mRNA isoforms of the SNARE Syntaxin/unc-64. In C. elegans mutants lacking unc-75 or its targets, regenerating axons form growth cones, yet are deficient in extension. Extending these findings to mammalian axon regeneration, we show that mouse Celf2 expression is upregulated after peripheral nerve injury and that Celf2 mutant mice are defective in axon regeneration. Further, mRNAs for several Syntaxins show CELF2 dependent regulation. Our data delineate a post-transcriptional regulatory pathway with a conserved role in regenerative axon extension.

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